This invention is concerned with 2-methoxyethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide, ##STR1## an ester having special value in the synthesis of piroxicam (4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide) ##STR2## an antiinflammatory agent of established value in the medicinal art. It will be noted that in past practice, the acyl radical of compounds of this type has been sometimes written as ##STR3## and such compounds alternatively named as 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine 1,1-dioxide derivatives. Those skilled in the art will understand that these are equivalent tautomeric forms of the same compound. The present invention is intended to encompass both tautomeric forms while writing only one of them as a matter of convenience.
Piroxicam was originally disclosed by Lombardino (U.S. Pat. No. 3,591,584). One of the processes for the synthesis of piroxicam disclosed therein is to react a 3-carboxylic acid ester with 2-aminopyridine. More specifically, the ester is disclosed as a (C.sub.1 -C.sub.12)alkyl ester or phenyl(C.sub.1 -C.sub.3)alkyl ester. The specific ester described is the methyl ester, viz. ##STR4## [See also Lombardino et al., J. Med. Chem. 14, pp. 1171-1175 (1971)]. A disadvantage in this otherwise useful process for piroxicam lies in the variable formation of quantities of a highly colored byproduct. This highly colored byproduct, which is removed only by multiple recrystallizations with major product loss, lends an unacceptable, strong yellow color to the piroxicam bulk product, even when present at very low levels (e.g., 0.5-1%). This byproduct has been isolated and determined to have the following structure: ##STR5## It has been shown that (IV) is actually formed as a byproduct in the reaction, rather than being derived from a contaminant in the precursor. How this compound is actually formed in the reaction mixture is not fully understood, although methods which are directed to rapid removal of the methanol byproduct as it is formed in the reaction appear to reduce the incidence of piroxicam batches having unacceptable color. However, these methods are of uncertain dependability and a goal has been to find an ester which is readily available by synthesis and which does not give rise to an ether such as (IV) as a troublesome byproduct during conversion to piroxicam.
Alternative syntheses of piroxicam which have been disclosed in the literature include reaction of 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine 1,1-dioxide with 2-pyridyl isocyanate (Lombardino, U.S. Pat. No. 3,591,584), transamidation of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxanilides with 2-aminopyridine (Lombardino, U.S. Pat. No. 3,891,637), cyclization of ##STR6## (Lombardino, U.S. Pat. No. 3,853,862), coupling of a 4-(C.sub.1 -C.sub.3)alkoxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxide with 2-aminopyridine followed by hydrolysis of the enolic ether linkage (Lombardino U.S. Pat. No. 3,892,740), coupling of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid, via the acid chloride, with 2-aminopyridine (Hammen, U.S. Pat. No. 4,100,347) and methylation of 4-hydroxy-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide (Canada Pat. No. 1,069,894).
Another ester related to the methoxyethyl ester of the present invention which has been specifically described in the literature is ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (Rasmussen, U.S. Pat. No. 3,501,466; see also Zinnes et al., U.S. Pat. No. 3,816,628).